GSK-3β-dependent downregulation of γ-taxilin and αNAC merge to regulate ER stress responses

The signaling pathway leading to the endoplasmic reticulum (ER) stress responses has not been fully elucidated. Here we showed that glycogen synthase kinase-3β (GSK-3β)-dependent downregulation of γ-taxilin and nascent polypeptide-associated complex α-subunit (αNAC) mediates hypoxia-induced unfolded protein responses (UPRs) and the subsequent apoptotic and autophagic pathways. The degradation of γ-taxilin or αNAC was sufficient to initiate UPRs in normoxic cells. However, the ER stress signaling pathways initiated by γ-taxilin or αNAC were distinct, triggering different ER stress sensors and activating different downstream pathways. Hypoxia caused GSK-3β-dependent tau hyperphosphorylation and cleavage in neuronal cells, but γ-taxilin ablation induced tau hyperphosphorylation alone and αNAC ablation induced neither changes. Notably, downregulation of γ-taxilin and αNAC occurs in the brain of patients with Alzheimer\u27s disease. These results suggest that GSK-3β-dependent downregulation of γ-taxilin and αNAC, which differently activate the UPRs, merge to regulate hypoxia-induced ER stress responses and provide a new insight into the pathogenesis of neurodegenerative diseases

A natural BH3 mimetic induces autophagy in apoptosis-resistant prostate cancer via modulating Bcl-2–Beclin1 interaction at endoplasmic reticulum

A natural BH3-mimetic, small-molecule inhibitor of Bcl-2, (−)-gossypol, shows promise in ongoing phase II and III clinical trials for human prostate cancer. In this study we show that (−)-gossypol preferentially induces autophagy in androgen-independent (AI) prostate cancer cells that have high levels of Bcl-2 and are resistant to apoptosis, both in vitro and in vivo, but not in androgen-dependent (AD) cells with low Bcl-2 and sensitive to apoptosis. The Bcl-2 inhibitor induces autophagy through blocking Bcl-2–Beclin1 interaction, together with downregulating Bcl-2, upregulating Beclin1, and activating the autophagic pathway. The (−)-gossypol-induced autophagy is dependent on Beclin1 and Atg5. Our results show for the first time that (−)-gossypol can also interrupt the interactions between Beclin1 and Bcl-2/Bcl-xL at endoplasmic reticulum, thus releasing the BH3-only pro-autophagic protein Beclin1, which in turn triggers the autophagic cascade. Oral administration of (−)-gossypol significantly inhibited the growth of AI prostate cancer xenografts, representing a promising new regimen for the treatment of human hormone-refractory prostate cancer with Bcl-2 overexpression. Our data provide new insights into the mode of cell death induced by Bcl-2 inhibitors, which will facilitate the rational design of clinical trials by selecting patients who are most likely to benefit from the Bcl-2-targeted molecular therapy

Geology, geochemistry, and some genetic discussion of the Chador-Malu iron oxide-apatite deposit, Bafq District, Central Iran

© 2015, Saudi Society for Geosciences.The Chador-Malu iron oxide-apatite system (Bafq District, Central Iran) contains the largest known iron ore deposit in Iran (pre-mining reserve of 400 Mt @ 55 % Fe), and comprises the pipe-like northern (this study) and the sill-like southern orebodies of predominantly massive ore, and a sodic-calcic alteration envelope. The geology and geochemistry of the Chador-Malu deposit demonstrates its similar characteristics to the Kiruna-type deposits. There is circumstantial evidence for rare earth elements (REE) mobilization during apatite leaching by high-temperature fluids and associated monazite nucleation. Pervasive actinolitization of the rhyolitic country rocks led to the formation of actinolite-rich metasomatic host rocks, which represent another evidence for high-temperature fluids at Chador-Malu. Hydrothermal mineralization is suggested by small iron ore veins (2–3 cm thick) and breccias cemented by iron oxides, as well as a Fe-metasomatism which overprints all types of host rock alteration. Based on REE geochemistry and spatial relationships, it is proposed that a potential source for metals and P could be late-stage Fe-P melt differentiates of the Cambrian magmatism, which is consistent with the late Fe-metasomatism of the host rocks. The proposed Fe-P melts and the mineralization would be linked by hydrothermal media through the zones of ring fracture at Chador-Malu and similar parts of the Bafq district